The proposed research is aimed at the understanding of the structure- activity relationship of metallocene anti-tumor agents The long term objective is using the structure-activity relationship, to synthesize active ligands (L). The initial study is focused on the synthesis, physico-chemical characterization and biological activity profile of CP2TiCIL and CP2TiL2 derivatives containing antimetabolites as ligands. The parent compound CP2TiCI2 is active against colorectal, lung and beast carcinomas therefore, the new derivatives may have similar have similar anti-tumor activity. However, their activity will be determined by mean of the biological activity study. The specific objectives of this study are: 1) Synthesis and characterization of new titanocene complexes containing modified DNA and RNA bases. This will be accomplished by replacing CI- for 6-thioguanine, 6-thiopurine, 2- thuouracil, 2-thiocytosine, allopurinol and 5-fluorouracil as ligands. Due to synergism, the proposed complexes are expected to be highly active anti-tumor agents, since they contain two antitumor agents in one unit compound. 2) Kinetics of ligand hydrolysis (CP and L). This will be monitored by conductance measurements and UV-VIS and 1H NMR spectroscopies. This objective provides vital information regarding to the stability and decomposition pattern of these complexes in aqueous solution. 3) DNA-Metallocene interaction studies will be pursued in order to gain insights with regard to the mechanism of action, binding constants and related thermodynamic parameters. The purpose of this drug binding study is to determine the affinity of the new synthesized complexes to DNA and to explore how this affinity changes as we change the structure (ligands) of the complexes. 4) Biological screening of new titanocene complexes. Biological screening of new synthesized titanocene complexes will be performed at the National Cancer Institute. The screening efforts are intended to find titanocene complexes with potential therapeutic uses. This research will afford valuable information to the understanding of chemical for the rational design of new organometallic antineoplastic agents. This proposal was originally submitted a part of the MBRS program at the InterAmerican University of Puerto Rico but the PI was relocated to UPRM.